In the lower airways, the activity of airway smooth muscle, microvasculature, and glands and, consequently, air flow to the lungs, is regulated predominantly by the parasympathetic nervous system. Over the past decade, we have demonstrated that airway parasympathetic ganglionic neurons regulate input (preganglionic) from the central nervous system and how this is altered by neighboring nerves or by inflammation. In this proposal, we will address hypotheses related to how neurotrophins, especially nerve growth factor (NGF), regulate the function of adult airway parasympathetic neurons. Neurotrophins, such as NGF, are increased in the inflamed or infected airways and many symptoms of these diseases (hyperactivity, cough, mucous production) may be related to altered or aberrant functions of the airway nervous system as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Neurotrophins function during development, particularly as survival factors, but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves (NGF, BDNF, NT-4/5 and NT-3) and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally indicating that their function goes far beyond their role in development. We propose to study their role in modulating the airway parasympathetic nervous system in adult animals (mice) and in humans. In Specific Aim 1, we will evaluate the mechanisms by which NGF increase synaptic efficacy at airway parasympathetic ganglia;in this aim, we will directly address hypotheses related to NGF-induced changes in synaptic transmission in mouse and human pig bronchial parasympathetic ganglia as well as hypotheses pertaining to the mechanisms by which neurotrophins modulate the action potential. In Aim 2, we'll determine how neurotrophins regulate the anatomy and neurotransmitter phenotype of airway neurons in mouse and human excitatory cholinergic and inhibitory neurons. In this Aim, we will address hypotheses relating to the changes in dendritic structure that occur with chronic exposure to NGF (and potentially, other neurotrophins), and address the hypothesis that neurotrophins can modulate the function of parasympathetic nerves by altering the neurotransmitter(s) they release. Results from these studies will shed new light on the complex pathophysiology of airway diseases such as asthma and COPD and may ultimately determine new therapeutic treatments for these complex diseases. PROJECT NARRATIVE: Air flows to the lungs through the trachea and bronchi and this airflow is predominately regulated by the parasympathetic nervous system. Certain molecules, call neurotrophins, especially nerve growth factor (NGF), are increased in the inflamed or infected airways and many symptoms of these diseases may be related to changes in parasympathetic nerves that then cause decreased airflow to the lungs as seen in asthma, chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Our research will directly address how NGF and other neurotrophins change the airway parasympathetic nervous system.